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  • The EMBO Journal (2005) 24, 3482 - 3492
  • doi:10.1038/sj.emboj.7600819

Published online: 15 September 2005

Novel role of p53 in maintaining mitochondrial genetic stability through interaction with DNA Pol big gamma

Geetha Achanta1,a, Ryohei Sasaki1,ab, Li Feng1, Jennifer S Carew1, Weiqin Lu1, Helene Pelicano1, Michael J Keating2 and Peng Huang1

  1. Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  2. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence to:

Peng Huang, Department of Molecular Pathology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Tel.: +1 713 792 7742; Fax: +1 713 794 4672; E-mail: phuang@mdanderson.org

aThese authors contributed equally to this work

bPresent address: Division of Radiology, Kobe University Graduate School of Medicine, Kobe City, Hyogo 650-0017, Japan

Received 14 April 2005; Accepted 24 August 2005

Mitochondrial DNA (mtDNA) mutations and deletions are frequently observed in cancer, and contribute to altered energy metabolism, increased reactive oxygen species (ROS), and attenuated apoptotic response to anticancer agents. The mechanisms by which cells maintain mitochondrial genomic integrity and the reason why cancer cells exhibit more frequent mtDNA mutations remain unclear. Here, we report that the tumor suppressor molecule p53 has a novel role in maintaining mitochondrial genetic stability through its ability to translocate to mitochondria and interact with mtDNA polymerase gamma (pol gamma) in response to mtDNA damage induced by exogenous and endogenous insults including ROS. The p53 protein physically interacts with mtDNA and pol gamma, and enhances the DNA replication function of pol gamma. Loss of p53 results in a significant increase in mtDNA vulnerability to damage, leading to increased frequency of in vivo mtDNA mutations, which are reversed by stable transfection of wild-type p53. This study provides a mechanistic explanation for the accelerating genetic instability and increased ROS stress in cancer cells associated with loss of p53.

  • Keywords:

    • DNA polymerase gamma,
    • mitochondria,
    • mutation,
    • p53,
    • reactive oxygen species (ROS)